Bifunctional tridentate pyrazolyl containing ligands for re and tc tricarbonyl complexes

ABSTRACT

The present invention relates to a chelating agent of the general formula: (I), wherein m is 0 or 1; X is NR 4  or S; Y is SR 5 , NHR 5  or P(R 5 ) 2 ; R 1  and R 3  are the same or different and are selected from H, alkyl or aryl; R 2  is H, COOH, NHR 6  or (CH 2 ) n COOR 6 ; R 4  is H, alkyl, aryl, (CH 2 ) n COOR 6  or (CH2) n OR 6 ; R 5  is H, alkyl, aryl, (CH 2 ) n COOR 6  or (CH 2 ) n OR 6 , R 6  is H, alkyl or aryl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and when R 1 ═R 3 ═CH 3 , R 2 , R 4  and R 5  are not all three H. The invention further relates to a method and kit for the preparation of radiolabeled biomolecules while using the chelating agent.

This invention lies in the field of radiopharmaceuticals and providesnew chelating agents to link biomolecules and carbonyl moieties forlabeling with technetium and rhenium. In particular the inventionrelates to bifunctional tridentate pyrazolyl-polyamines,pyrazolyl-aminothioethers, pyrazolyl-polythioethers,pyrazolyl-aminophosphines and pyrazolyl-thioetherphosphines whichstabilize the moieties [M(CO)₃]⁺ (M=Re, Tc, Mn) and bind to biomoleculeswhich accumulate in diseased tissues. The invention relates to thechelators as such, to chelators coupled to a biomolecule and to eitherof these complexed with carbonyl. In addition the invention relates to akit for providing radiolabeled biomolecules and to the use of suchradiolabeled molecules in diagnosis and therapy.

The diagnosis and therapy of cancer still needs a significant input fromthe chemical, radiochemical and pharmaceutical point of view. Tumourseeking compounds stable in vitro and in vivo, with high specificactivity and specificity are still an important issue in theradiopharmaceutical field. Since the publication of internationalpatents on [Re(CO)₃]⁺ and [Tc(CO)₃]⁺ [1] a significant interest hasappeared in this oxidation state, which opens new perspectives onpharmaceutical and Nuclear Medicine fields. The search for new chelatingagents is essential as they are determinant for the uptake of biologicalvectors. Several chelating agents have been described in patents [1, 2]and publications [3, 4, 5].

It is the object of the present invention to enlarge the family ofbifunctional chelating agents.

This is achieved by the invention by chelating agents of the generalformula:

wherein m is 0 or 1;

-   X is NR₄ or S;-   Y is SR₅, NHR₅ or P(R₅)₂;-   R₁ and R₃ are the same or different and are selected from H, alkyl    or aryl;-   R₂ is H, COOH, NHR₆ or (CH₂)_(n)COOR₆;-   R₄ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆;-   R₅ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆-   R₆ is H, alkyl or aryl;-   n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and-   when R₁═R₃═CH₃, R₂, R₄ and R₅ are not all three H.

These molecules combine two functions. One is for the stabilization ofmetal centers, including radioactive metals, and comprises differentdonor atom sets, and the other is a functional group for binding to themolecule of interest.

The alkyl is a C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl or C₆alkyl, in particular selected from methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, isohexyl (2-methylpentyl), neohexyl (2,2-dimethylbutyl),3-methylpentyl, 2,3-dimethylbutyl.

The aryls are monocyclic, C₅-C₈, or polycyclic C₁₀-C₁₈, and areoptionally substituted with alkyl, carboxy, oxo, amino, alkoxy oraldehyde groups.

n is 2, 3, 4, 5 or 6 and preferably 2, 3 or 4.

The chelating agent is for example a pyrazolyl-polyamine of the generalformula:

wherein R₁, R₂, R₃, R₄ and R₅ are as defined above.

Alternatively, the chelating agent is a pyrazolyl-aminothioether of thegeneral formula:

wherein R₁, R₂, R₃, R₄ and R₅ are as defined above.

In yet another embodiment the chelating agent is apyrazolyl-polythioether of the general formula:

wherein R₁, R₂, R₃, R₄ and R₅ are as defined above.

In yet another embodiment the chelating agent is apyrazolyl-aminophosphine of the general formula

wherein R₁, R₂, R₃, R₄ and R₅ are as defined above.

In a further embodiment the chelating agent is apyrazolyl-thioetherphosphine of the general formula:

wherein R₁, R₂, R₃, R₄ and R₅ are as defined above.

The invention provides more particularly chelating agents of formula I,wherein X and Y are N, R₆ is H, C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl,C₅ alkyl or C₆ alkyl, monocyclic aryls, preferably phenyl or benzyl, orpolycyclic C₁₀-C₁₈ aryls, optionally substituted with alkyl, carboxy,oxo amino, alkoxy or aldehyde groups, or a biomolecule and R₁, R₃, R₃,R₄ and R₅ are as listed in Table 1.

In another embodiment the invention relates to chelating agents offormula I, wherein X and Y are S, R₆ is H, C₁ alkyl, C₂ alkyl, C₃ alkyl,C₄ alkyl, C₅ alkyl or C₆ alkyl, monocyclic aryls, preferably phenyl orbenzyl, or polycyclic C₁₀-C₁₈ aryls, optionally substituted with alkyl,carboxy, oxo amino, alkoxy or aldehyde groups, or a biomolecule and R₁,R₂, R₃, R₄ and R₅ are as listed in Table 1.

In yet another embodiment chelating agents of formula I are provided,wherein X is N and Y is S, R₆ is H, C, alkyl, C₂ alkyl, C₃ alkyl, C₄alkyl, C₅ alkyl or C6 alkyl, monocyclic aryls, preferably phenyl orbenzyl, or polycyclic C₁₀-C₁₈ aryls, optionally substituted with alkyl,carboxy, oxo amino, alkoxy or aldehyde groups, or a biomolecule and R₁,R₂, R₃, R₄ and R₅ are as listed in Table 1.

According to a further aspect thereof the invention relates to chelatingagents of formula I, wherein X is S and Y are N, R₆ is H, C₁ alkyl, C₂alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl, monocyclic aryls,preferably phenyl or benzyl, or polycyclic C₁₀-C₁₈ aryls, optionallysubstituted with alkyl, carboxy, oxo amino, alkoxy or aldehyde groups,or a biomolecule and R₁, R₂, R₃, R₄ and R₅ are as listed in Table 1.

According to another aspect of the invention, chelating agents offormula I are provided, wherein X is N and Y is P, R₆ is H, C₁ alkyl, C₂alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl, monocyclic aryls,preferably phenyl or benzyl, or polycyclic C₁₀-C₁₈ aryls, optionallysubstituted with alkyl, carboxy, oxo amino, alkoxy or aldehyde groups,or a biomolecule and R₁, R₂, R₃, R₄ and R₅ are as listed in Table 1.

In another embodiment the invention relates to chelating agents offormula I, wherein X is S and Y is P, R₆ is H, C₁ alkyl, C₂ alkyl, C₃alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl, monocyclic aryls, preferablyphenyl or benzyl, or polycyclic C₁₀-C₁₈ aryls, optionally substitutedwith alkyl, carboxy, oxo amino, alkoxy or aldehyde groups, or abiomolecule and R₁, R₂, R₃, R₄ and R₅ are as listed in Table 1.

The chelating agents of the invention are particularly suited to linkbiomolecules with carbonyl moieties in order to arrive at labeledbiomolecules having a high specificity for the target. In formula I R₆can thus be a biomolecule.

The possible positions of the biomolecules (BM) are shown in FIG. 1.

The biomolecule can be anything that is useful in the treatment anddiagnosis of tumors and can be coupled to the chelators of theinvention. The skilled person will be able to establish for whichbiomolecules the chelators of the invention can be used. In particularthe biomolecule is selected from amino acids, peptides, proteins,oligonucleotides, polynucleotides, sugars.

More specifically, the biomolecule is selected from the group consistingof antibodies, ligands of tumor receptors, such as CCK, thioglucose,glucosamine, somatostatin, neurotensin, bombesin, CCK, annexin,interleukins, growth factors, steroid hormones and molecules binding toGPIIb/IIIa receptors. Other biomolecules can be glucose, thioglucose,neurotransmitters, inhibitors of the tyrosine kinase activity such asbenzothiopyranones, anilinophthalimides, quinazolines, pyridopyrimidinesand pyrrolopyrimidines.

Particular agents of the invention are the following:

All of the chelating agents, either with or without a biomoleculecoupled thereto can be complexed with a carbonyl moiety of the formula[M(CO)₃)⁺, wherein M is rhenium (Re), technetium (Tc) or Manganese (Mn).

The chelating agents of the invention are molecules according to formulaI wherein X and Y can be either N and N, N and S, S and N, S and S, Nand P, or S and P. Each of these combinations can be combined withvarious combinations of R₁, R₂, R₃, R₄ and R₅. All possible combinationsof R₁, R₂, R₃, R₄ and R₅ are listed in Table 1. In Table 1 alkyl is a C₁alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl, in particularselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl(2-methylpentyl), neohexyl (2,2-dimethylbutyl), 3-methylpentyl,2,3-dimethylbutyl; the aryl is monocyclic, C₅-C₈, or polycyclic,C₁₀-C₁₈, and optionally substituted with alkyl, carboxy, oxo, amino,alkoxy or aldehyde groups and is in particular phenyl or benzyl, and nis 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. R₆ is H, alkyl, aryl or abiomolecule as defined above. Substituting each of the above variablesinto the table will give all compounds of claim 1 that are herewithdisclosed. TABLE 1 R1 R2 R3 R4 R5 H H H H H H H H H alkyl H H H H aryl HH H H (CH₂)_(n)COOR₆ H H H H (CH₂)_(n)OR₆ H H H alkyl H H H H alkylalkyl H H H alkyl aryl H H H alkyl (CH₂)_(n)COOR₆ H H H alkyl(CH₂)_(n)OR₆ H H H aryl H H H H aryl alkyl H H H aryl aryl H H H aryl(CH₂)_(n)COOR₆ H H H aryl (CH₂)_(n)OR₆ H H H (CH₂)_(n)COOR₆ H H H H(CH₂)_(n)COOR₆ alkyl H H H (CH₂)_(n)COOR₆ aryl H H H (CH₂)_(n)COOR₆(CH₂)_(n)COOR₆ H H H (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ H H H (CH₂)_(n)OR₆ H HH H (CH₂)_(n)OR₆ alkyl H H H (CH₂)_(n)OR₆ aryl H H H (CH₂)_(n)OR₆(CH₂)_(n)COOR₆ H H H (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ H H alkyl H H H H alkyl Halkyl H H alkyl H aryl H H alkyl H (CH₂)_(n)COOR₆ H H alkyl H(CH₂)_(n)OR₆ H H alkyl alkyl H H H alkyl alkyl alkyl H H alkyl alkylaryl H H alkyl alkyl (CH₂)_(n)COOR₆ H H alkyl alkyl (CH₂)_(n)OR₆ H Halkyl aryl H H H alkyl aryl alkyl H H alkyl aryl aryl H H alkyl aryl(CH₂)_(n)COOR₆ H H alkyl aryl (CH₂)_(n)OR₆ H H alkyl (CH₂)_(n)COOR₆ H HH alkyl (CH₂)_(n)COOR₆ alkyl H H alkyl (CH₂)_(n)COOR₆ aryl H H alkyl(CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ H H alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ H Halkyl (CH₂)_(n)OR₆ H H H alkyl (CH₂)_(n)OR₆ alkyl H H alkyl (CH₂)_(n)OR₆aryl H H alkyl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H H alkyl (CH₂)_(n)OR₆(CH₂)_(n)OR₆ H H aryl H H H H aryl H alkyl H H aryl H aryl H H aryl H(CH₂)_(n)COOR₆ H H aryl H (CH₂)_(n)OR₆ H H aryl alkyl H H H aryl alkylalkyl H H aryl alkyl aryl H H aryl alkyl (CH₂)_(n)COOR₆ H H aryl alkyl(CH₂)_(n)OR₆ H H aryl aryl H H H aryl aryl alkyl H H aryl aryl aryl H Haryl aryl (CH₂)_(n)COOR₆ H H aryl aryl (CH₂)_(n)OR₆ H H aryl(CH₂)_(n)COOR₆ H H H aryl (CH₂)_(n)COOR₆ alkyl H H aryl (CH₂)_(n)COOR₆aryl H H aryl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ H H aryl (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ H H aryl (CH₂)_(n)OR₆ H H H aryl (CH₂)_(n)OR₆ alkyl H Haryl (CH₂)_(n)OR₆ aryl H H aryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H H aryl(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ H COOH H H H H COOH H H alkyl H COOH H H arylH COOH H H (CH₂)_(n)COOR₆ H COOH H H (CH₂)_(n)OR₆ H COOH H alkyl H HCOOH H alkyl alkyl H COOH H alkyl aryl H COOH H alkyl (CH₂)_(n)COOR₆ HCOOH H alkyl (CH₂)_(n)OR₆ H COOH H aryl H H COOH H aryl alkyl H COOH Haryl aryl H COOH H aryl (CH₂)_(n)COOR₆ H COOH H aryl (CH₂)_(n)OR₆ H COOHH (CH₂)_(n)COOR₆ H H COOH H (CH₂)_(n)COOR₆ alkyl H COOH H (CH₂)_(n)COOR₆aryl H COOH H (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ H COOH H (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ H COOH H (CH₂)_(n)OR₆ H H COOH H (CH₂)_(n)OR₆ alkyl H COOHH (CH₂)_(n)OR₆ aryl H COOH H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H COOH H(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ H COOH alkyl H H H COOH alkyl H alkyl H COOHalkyl H aryl H COOH alkyl H (CH₂)_(n)COOR₆ H COOH alkyl H (CH₂)_(n)OR₆ HCOOH alkyl alkyl H H COOH alkyl alkyl alkyl H COOH alkyl alkyl aryl HCOOH alkyl alkyl (CH₂)_(n)COOR₆ H COOH alkyl alkyl (CH₂)_(n)OR₆ H COOHalkyl aryl H H COOH alkyl aryl alkyl H COOH alkyl aryl aryl H COOH alkylaryl (CH₂)_(n)COOR₆ H COOH alkyl aryl (CH₂)_(n)OR₆ H COOH alkyl(CH₂)_(n)COOR₆ H H COOH alkyl (CH₂)_(n)COOR₆ alkyl H COOH alkyl(CH₂)_(n)COOR₆ aryl H COOH alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ H COOHalkyl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ H COOH alkyl (CH₂)_(n)OR₆ H H COOHalkyl (CH₂)_(n)OR₆ alkyl H COOH alkyl (CH₂)_(n)OR₆ aryl H COOH alkyl(CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H COOH alkyl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ HCOOH aryl H H H COOH aryl H alkyl H COOH aryl H aryl H COOH aryl H(CH₂)_(n)COOR₆ H COOH aryl H (CH₂)_(n)OR₆ H COOH aryl alkyl H H COOHaryl alkyl alkyl H COOH aryl alkyl aryl H COOH aryl alkyl (CH₂)_(n)COOR₆H COOH aryl alkyl (CH₂)_(n)OR₆ H COOH aryl aryl H H COOH aryl aryl alkylH COOH aryl aryl aryl H COOH aryl aryl (CH₂)_(n)COOR₆ H COOH aryl aryl(CH₂)_(n)OR₆ H COOH aryl (CH₂)_(n)COOR₆ H H COOH aryl (CH₂)_(n)COOR₆alkyl H COOH aryl (CH₂)_(n)COOR₆ aryl H COOH aryl (CH₂)_(n)COOR₆(CH₂)_(n)COOR₆ H COOH aryl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ H COOH aryl(CH₂)_(n)OR₆ H H COOH aryl (CH₂)_(n)OR₆ alkyl H COOH aryl (CH₂)_(n)OR₆aryl H COOH aryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H COOH aryl (CH₂)_(n)OR₆(CH₂)_(n)OR₆ H NHR₆ H H H H NHR₆ H H alkyl H NHR₆ H H aryl H NHR₆ H H(CH₂)_(n)COOR₆ H NHR₆ H H (CH₂)_(n)OR₆ H NHR₆ H alkyl H H NHR₆ H alkylalkyl H NHR₆ H alkyl aryl H NHR₆ H alkyl (CH₂)_(n)COOR₆ H NHR₆ H alkyl(CH₂)_(n)OR₆ H NHR₆ H aryl H H NHR₆ H aryl alkyl H NHR₆ H aryl aryl HNHR₆ H aryl (CH₂)_(n)COOR₆ H NHR₆ H aryl (CH₂)_(n)OR₆ H NHR₆ H(CH₂)_(n)COOR₆ H H NHR₆ H (CH₂)_(n)COOR₆ alkyl H NHR₆ H (CH₂)_(n)COOR₆aryl H NHR₆ H (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ H NHR₆ H (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ H NHR₆ H (CH₂)_(n)OR₆ H H NHR₆ H (CH₂)_(n)OR₆ alkyl H NHR₆H (CH₂)_(n)OR₆ aryl H NHR₆ H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H NHR₆ H(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ H NHR₆ alkyl H H H NHR₆ alkyl H alkyl H NHR₆alkyl H aryl H NHR₆ alkyl H (CH₂)_(n)COOR₆ H NHR₆ alkyl H (CH₂)_(n)OR₆ HNHR₆ alkyl alkyl H H NHR₆ alkyl alkyl alkyl H NHR₆ alkyl alkyl aryl HNHR₆ alkyl alkyl (CH₂)_(n)COOR₆ H NHR₆ alkyl alkyl (CH₂)_(n)OR₆ H NHR₆alkyl aryl H H NHR₆ alkyl aryl alkyl H NHR₆ alkyl aryl aryl H NHR₆ alkylaryl (CH₂)_(n)COOR₆ H NHR₆ alkyl aryl (CH₂)_(n)OR₆ H NHR₆ alkyl(CH₂)_(n)COOR₆ H H NHR₆ alkyl (CH₂)_(n)COOR₆ alkyl H NHR₆ alkyl(CH₂)_(n)COOR₆ aryl H NHR₆ alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ H NHR₆alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ H NHR₆ alkyl (CH₂)_(n)OR₆ H H NHR₆alkyl (CH₂)_(n)OR₆ alkyl H NHR₆ alkyl (CH₂)_(n)OR₆ aryl H NHR₆ alkyl(CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H NHR₆ alkyl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ HNHR₆ aryl H H H NHR₆ aryl H alkyl H NHR₆ aryl H aryl H NHR₆ aryl H(CH₂)_(n)COOR₆ H NHR₆ aryl H (CH₂)_(n)OR₆ H NHR₆ aryl alkyl H H NHR₆aryl alkyl alkyl H NHR₆ aryl alkyl aryl H NHR₆ aryl alkyl (CH₂)_(n)COOR₆H NHR₆ aryl alkyl (CH₂)_(n)OR₆ H NHR₆ aryl aryl H H NHR₆ aryl aryl alkylH NHR₆ aryl aryl aryl H NHR₆ aryl aryl (CH₂)_(n)COOR₆ H NHR₆ aryl aryl(CH₂)_(n)OR₆ H NHR₆ aryl (CH₂)_(n)COOR₆ H H NHR₆ aryl (CH₂)_(n)COOR₆alkyl H NHR₆ aryl (CH₂)_(n)COOR₆ aryl H NHR₆ aryl (CH₂)_(n)COOR₆(CH₂)_(n)COOR₆ H NHR₆ aryl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ H NHR₆ aryl(CH₂)_(n)OR₆ H H NHR₆ aryl (CH₂)_(n)OR₆ alkyl H NHR₆ aryl (CH₂)_(n)OR₆aryl H NHR₆ aryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H NHR₆ aryl (CH₂)_(n)OR₆(CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ H H H H (CH₂)_(n)COOR₆ H H alkyl H(CH₂)_(n)COOR₆ H H aryl H (CH₂)_(n)COOR₆ H H (CH₂)_(n)COOR₆ H(CH₂)_(n)COOR₆ H H (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ H alkyl H H(CH₂)_(n)COOR₆ H alkyl alkyl H (CH₂)_(n)COOR₆ H alkyl aryl H(CH₂)_(n)COOR₆ H alkyl (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ H alkyl(CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ H aryl H H (CH₂)_(n)COOR₆ H aryl alkyl H(CH₂)_(n)COOR₆ H aryl aryl H (CH₂)_(n)COOR₆ H aryl (CH₂)_(n)COOR₆ H(CH₂)_(n)COOR₆ H aryl (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ H H(CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ alkyl H (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆aryl H (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ H(CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ H H(CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ alkyl H (CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ arylH (CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ H(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ alkyl H H H (CH₂)_(n)COOR₆alkyl H alkyl H (CH₂)_(n)COOR₆ alkyl H aryl H (CH₂)_(n)COOR₆ alkyl H(CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ alkyl H (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆alkyl alkyl H H (CH₂)_(n)COOR₆ alkyl alkyl alkyl H (CH₂)_(n)COOR₆ alkylalkyl aryl H (CH₂)_(n)COOR₆ alkyl alkyl (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆alkyl alkyl (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ alkyl aryl H H (CH₂)_(n)COOR₆alkyl aryl alkyl H (CH₂)_(n)COOR₆ alkyl aryl aryl H (CH₂)_(n)COOR₆ alkylaryl (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ alkyl aryl (CH₂)_(n)OR₆ H(CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ H H (CH₂)_(n)COOR₆ alkyl(CH₂)_(n)COOR₆ alkyl H (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ aryl H(CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ HH (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ alkyl H (CH₂)_(n)COOR₆ alkyl(CH₂)_(n)OR₆ aryl H (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ H(CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ aryl H HH (CH₂)_(n)COOR₆ aryl H alkyl H (CH₂)_(n)COOR₆ aryl H aryl H(CH₂)_(n)COOR₆ aryl H (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ aryl H(CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ aryl alkyl H H (CH₂)_(n)COOR₆ aryl alkylalkyl H (CH₂)_(n)COOR₆ aryl alkyl aryl H (CH₂)_(n)COOR₆ aryl alkyl(CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ aryl alkyl (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆aryl aryl H H (CH₂)_(n)COOR₆ aryl aryl alkyl H (CH₂)_(n)COOR₆ aryl arylaryl H (CH₂)_(n)COOR₆ aryl aryl (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ arylaryl (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ H H(CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ alkyl H (CH₂)_(n)COOR₆ aryl(CH₂)_(n)COOR₆ aryl H (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆H (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ H (CH₂)_(n)COOR₆ aryl(CH₂)_(n)OR₆ H H (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ alkyl H (CH₂)_(n)COOR₆aryl (CH₂)_(n)OR₆ aryl H (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆H (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ alkyl H H H H alkyl H HH alkyl alkyl H H H aryl alkyl H H H (CH₂)_(n)COOR₆ alkyl H H H(CH₂)_(n)OR₆ alkyl H H alkyl H alkyl H H alkyl alkyl alkyl H H alkylaryl alkyl H H alkyl (CH₂)_(n)COOR₆ alkyl H H alkyl (CH₂)_(n)OR₆ alkyl HH aryl H alkyl H H aryl alkyl alkyl H H aryl aryl alkyl H H aryl(CH₂)_(n)COOR₆ alkyl H H aryl (CH₂)_(n)OR₆ alkyl H H (CH₂)_(n)COOR₆ Halkyl H H (CH₂)_(n)COOR₆ alkyl alkyl H H (CH₂)_(n)COOR₆ aryl alkyl H H(CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ alkyl H H (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆alkyl H H (CH₂)_(n)OR₆ H alkyl H H (CH₂)_(n)OR₆ alkyl alkyl H H(CH₂)_(n)OR₆ aryl alkyl H H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ alkyl H H(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ alkyl H alkyl H H alkyl H alkyl H alkyl alkylH alkyl H aryl alkyl H alkyl H (CH₂)_(n)COOR₆ alkyl H alkyl H(CH₂)_(n)OR₆ alkyl H alkyl alkyl H alkyl H alkyl alkyl alkyl alkyl Halkyl alkyl aryl alkyl H alkyl alkyl (CH₂)_(n)COOR₆ alkyl H alkyl alkyl(CH₂)_(n)OR₆ alkyl H alkyl aryl H alkyl H alkyl aryl alkyl alkyl H alkylaryl aryl alkyl H alkyl aryl (CH₂)_(n)COOR₆ alkyl H alkyl aryl(CH₂)_(n)OR₆ alkyl H alkyl (CH₂)_(n)COOR₆ H alkyl H alkyl (CH₂)_(n)COOR₆alkyl alkyl H alkyl (CH₂)_(n)COOR₆ aryl alkyl H alkyl (CH₂)_(n)COOR₆(CH₂)_(n)COOR₆ alkyl H alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ alkyl H alkyl(CH₂)_(n)OR₆ H alkyl H alkyl (CH₂)_(n)OR₆ alkyl alkyl H alkyl(CH₂)_(n)OR₆ aryl alkyl H alkyl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ alkyl Halkyl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ alkyl H aryl H H alkyl H aryl H alkylalkyl H aryl H aryl alkyl H aryl H (CH₂)_(n)COOR₆ alkyl H aryl H(CH₂)_(n)OR₆ alkyl H aryl alkyl H alkyl H aryl alkyl alkyl alkyl H arylalkyl aryl alkyl H aryl alkyl (CH₂)_(n)COOR₆ alkyl H aryl alkyl(CH₂)_(n)OR₆ alkyl H aryl aryl H alkyl H aryl aryl alkyl alkyl H arylaryl aryl alkyl H aryl aryl (CH₂)_(n)COOR₆ alkyl H aryl aryl(CH₂)_(n)OR₆ alkyl H aryl (CH₂)_(n)COOR₆ H alkyl H aryl (CH₂)_(n)COOR₆alkyl alkyl H aryl (CH₂)_(n)COOR₆ aryl alkyl H aryl (CH₂)_(n)COOR₆(CH₂)_(n)COOR₆ alkyl H aryl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ alkyl H aryl(CH₂)_(n)OR₆ H alkyl H aryl (CH₂)_(n)OR₆ alkyl alkyl H aryl (CH₂)_(n)OR₆aryl alkyl H aryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ alkyl H aryl (CH₂)_(n)OR₆(CH₂)_(n)OR₆ alkyl COOH H H H alkyl COOH H H alkyl alkyl COOH H H arylalkyl COOH H H (CH₂)_(n)COOR₆ alkyl COOH H H (CH₂)_(n)OR₆ alkyl COOH Halkyl H alkyl COOH H alkyl alkyl alkyl COOH H alkyl aryl alkyl COOH Halkyl (CH₂)_(n)COOR₆ alkyl COOH H alkyl (CH₂)_(n)OR₆ alkyl COOH H aryl Halkyl COOH H aryl alkyl alkyl COOH H aryl aryl alkyl COOH H aryl(CH₂)_(n)COOR₆ alkyl COOH H aryl (CH₂)_(n)OR₆ alkyl COOH H(CH₂)_(n)COOR₆ H alkyl COOH H (CH₂)_(n)COOR₆ alkyl alkyl COOH H(CH₂)_(n)COOR₆ aryl alkyl COOH H (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ alkylCOOH H (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ alkyl COOH H (CH₂)_(n)OR₆ H alkylCOOH H (CH₂)_(n)OR₆ alkyl alkyl COOH H (CH₂)_(n)OR₆ aryl alkyl COOH H(CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ alkyl COOH H (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ alkylCOOH alkyl H H alkyl COOH alkyl H alkyl alkyl COOH alkyl H aryl alkylCOOH alkyl H (CH₂)_(n)COOR₆ alkyl COOH alkyl H (CH₂)_(n)OR₆ alkyl COOHalkyl alkyl H alkyl COOH alkyl alkyl alkyl alkyl COOH alkyl alkyl arylalkyl COOH alkyl alkyl (CH₂)_(n)COOR₆ alkyl COOH alkyl alkyl(CH₂)_(n)OR₆ alkyl COOH alkyl aryl H alkyl COOH alkyl aryl alkyl alkylCOOH alkyl aryl aryl alkyl COOH alkyl aryl (CH₂)_(n)COOR₆ alkyl COOHalkyl aryl (CH₂)_(n)OR₆ alkyl COOH alkyl (CH₂)_(n)COOR₆ H alkyl COOHalkyl (CH₂)_(n)COOR₆ alkyl alkyl COOH alkyl (CH₂)_(n)COOR₆ aryl alkylCOOH alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ alkyl COOH alkyl (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ alkyl COOH alkyl (CH₂)_(n)OR₆ H alkyl COOH alkyl(CH₂)_(n)OR₆ alkyl alkyl COOH alkyl (CH₂)_(n)OR₆ aryl alkyl COOH alkyl(CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ alkyl COOH alkyl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆alkyl COOH aryl H H alkyl COOH aryl H alkyl alkyl COOH aryl H aryl alkylCOOH aryl H (CH₂)_(n)COOR₆ alkyl COOH aryl H (CH₂)_(n)OR₆ alkyl COOHaryl alkyl H alkyl COOH aryl alkyl alkyl alkyl COOH aryl alkyl arylalkyl COOH aryl alkyl (CH₂)_(n)COOR₆ alkyl COOH aryl alkyl (CH₂)_(n)OR₆alkyl COOH aryl aryl H alkyl COOH aryl aryl alkyl alkyl COOH aryl arylaryl alkyl COOH aryl aryl (CH₂)_(n)COOR₆ alkyl COOH aryl aryl(CH₂)_(n)OR₆ alkyl COOH aryl (CH₂)_(n)COOR₆ H alkyl COOH aryl(CH₂)_(n)COOR₆ alkyl alkyl COOH aryl (CH₂)_(n)COOR₆ aryl alkyl COOH aryl(CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ alkyl COOH aryl (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ alkyl COOH aryl (CH₂)_(n)OR₆ H alkyl COOH aryl (CH₂)_(n)OR₆alkyl alkyl COOH aryl (CH₂)_(n)OR₆ aryl alkyl COOH aryl (CH₂)_(n)OR₆(CH₂)_(n)COOR₆ alkyl COOH aryl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ alkyl NHR₆ H HH alkyl NHR₆ H H alkyl alkyl NHR₆ H H aryl alkyl NHR₆ H H (CH₂)_(n)COOR₆alkyl NHR₆ H H (CH₂)_(n)OR₆ alkyl NHR₆ H alkyl H alkyl NHR₆ H alkylalkyl alkyl NHR₆ H alkyl aryl alkyl NHR₆ H alkyl (CH₂)_(n)COOR₆ alkylNHR₆ H alkyl (CH₂)_(n)OR₆ alkyl NHR₆ H aryl H alkyl NHR₆ H aryl alkylalkyl NHR₆ H aryl aryl alkyl NHR₆ H aryl (CH₂)_(n)COOR₆ alkyl NHR₆ Haryl (CH₂)_(n)OR₆ alkyl NHR₆ H (CH₂)_(n)COOR₆ H alkyl NHR₆ H(CH₂)_(n)COOR₆ alkyl alkyl NHR₆ H (CH₂)_(n)COOR₆ aryl alkyl NHR₆ H(CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ alkyl NHR₆ H (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆alkyl NHR₆ H (CH₂)_(n)OR₆ H alkyl NHR₆ H (CH₂)_(n)OR₆ alkyl alkyl NHR₆ H(CH₂)_(n)OR₆ aryl alkyl NHR₆ H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ alkyl NHR₆ H(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ alkyl NHR₆ alkyl H H alkyl NHR₆ alkyl H alkylalkyl NHR₆ alkyl H aryl alkyl NHR₆ alkyl H (CH₂)_(n)COOR₆ alkyl NHR₆alkyl H (CH₂)_(n)OR₆ alkyl NHR₆ alkyl alkyl H alkyl NHR₆ alkyl alkylalkyl alkyl NHR₆ alkyl alkyl aryl alkyl NHR₆ alkyl alkyl (CH₂)_(n)COOR₆alkyl NHR₆ alkyl alkyl (CH₂)_(n)OR₆ alkyl NHR₆ alkyl aryl H alkyl NHR₆alkyl aryl alkyl alkyl NHR₆ alkyl aryl aryl alkyl NHR₆ alkyl aryl(CH₂)_(n)COOR₆ alkyl NHR₆ alkyl aryl (CH₂)_(n)OR₆ alkyl NHR₆ alkyl(CH₂)_(n)COOR₆ H alkyl NHR₆ alkyl (CH₂)_(n)COOR₆ alkyl alkyl NHR₆ alkyl(CH₂)_(n)COOR₆ aryl alkyl NHR₆ alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ alkylNHR₆ alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ alkyl NHR₆ alkyl (CH₂)_(n)OR₆ Halkyl NHR₆ alkyl (CH₂)_(n)OR₆ alkyl alkyl NHR₆ alkyl (CH₂)_(n)OR₆ arylalkyl NHR₆ alkyl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ alkyl NHR₆ alkyl(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ alkyl NHR₆ aryl H H alkyl NHR₆ aryl H alkylalkyl NHR₆ aryl H aryl alkyl NHR₆ aryl H (CH₂)_(n)COOR₆ alkyl NHR₆ arylH (CH₂)_(n)OR₆ alkyl NHR₆ aryl alkyl H alkyl NHR₆ aryl alkyl alkyl alkylNHR₆ aryl alkyl aryl alkyl NHR₆ aryl alkyl (CH₂)_(n)COOR₆ alkyl NHR₆aryl alkyl (CH₂)_(n)OR₆ alkyl NHR₆ aryl aryl H alkyl NHR₆ aryl arylalkyl alkyl NHR₆ aryl aryl aryl alkyl NHR₆ aryl aryl (CH₂)_(n)COOR₆alkyl NHR₆ aryl aryl (CH₂)_(n)OR₆ alkyl NHR₆ aryl (CH₂)_(n)COOR₆ H alkylNHR₆ aryl (CH₂)_(n)COOR₆ alkyl alkyl NHR₆ aryl (CH₂)_(n)COOR₆ aryl alkylNHR₆ aryl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ alkyl NHR₆ aryl (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ alkyl NHR₆ aryl (CH₂)_(n)OR₆ H alkyl NHR₆ aryl (CH₂)_(n)OR₆alkyl alkyl NHR₆ aryl (CH₂)_(n)OR₆ aryl alkyl NHR₆ aryl (CH₂)_(n)OR₆(CH₂)_(n)COOR₆ alkyl NHR₆ aryl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ alkyl(CH₂)_(n)COOR₆ H H H alkyl (CH₂)_(n)COOR₆ H H alkyl alkyl (CH₂)_(n)COOR₆H H aryl alkyl (CH₂)_(n)COOR₆ H H (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ HH (CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ H alkyl H alkyl (CH₂)_(n)COOR₆ Halkyl alkyl alkyl (CH₂)_(n)COOR₆ H alkyl aryl alkyl (CH₂)_(n)COOR₆ Halkyl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ H alkyl (CH₂)_(n)OR₆ alkyl(CH₂)_(n)COOR₆ H aryl H alkyl (CH₂)_(n)COOR₆ H aryl alkyl alkyl(CH₂)_(n)COOR₆ H aryl aryl alkyl (CH₂)_(n)COOR₆ H aryl (CH₂)_(n)COOR₆alkyl (CH₂)_(n)COOR₆ H aryl (CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ H(CH₂)_(n)COOR₆ H alkyl (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ alkyl alkyl(CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ aryl alkyl (CH₂)_(n)COOR₆ H(CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ H alkyl (CH₂)_(n)COOR₆H (CH₂)_(n)OR₆ alkyl alkyl (CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ aryl alkyl(CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ H(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ alkyl H H alkyl(CH₂)_(n)COOR₆ alkyl H alkyl alkyl (CH₂)_(n)COOR₆ alkyl H aryl alkyl(CH₂)_(n)COOR₆ alkyl H (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ alkyl H(CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ alkyl alkyl H alkyl (CH₂)_(n)COOR₆alkyl alkyl alkyl alkyl (CH₂)_(n)COOR₆ alkyl alkyl aryl alkyl(CH₂)_(n)COOR₆ alkyl alkyl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ alkylalkyl (CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ alkyl aryl H alkyl(CH₂)_(n)COOR₆ alkyl aryl alkyl alkyl (CH₂)_(n)COOR₆ alkyl aryl arylalkyl (CH₂)_(n)COOR₆ alkyl aryl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆alkyl aryl (CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ Halkyl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ alkyl alkyl (CH₂)_(n)COOR₆alkyl (CH₂)_(n)COOR₆ aryl alkyl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆(CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆alkyl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ H alkyl (CH₂)_(n)COOR₆ alkyl(CH₂)_(n)OR₆ alkyl alkyl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ aryl alkyl(CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆alkyl (CH₂)_(n)COR₆ (CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ aryl H H alkyl(CH₂)_(n)COOR₆ aryl H alkyl alkyl (CH₂)_(n)COOR₆ aryl H aryl alkyl(CH₂)_(n)COOR₆ aryl H (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ aryl H(CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ aryl alkyl H alkyl (CH₂)_(n)COOR₆ arylalkyl alkyl alkyl (CH₂)_(n)COOR₆ aryl alkyl aryl alkyl (CH₂)_(n)COOR₆aryl alkyl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ aryl alkyl (CH₂)_(n)OR₆alkyl (CH₂)_(n)COOR₆ aryl aryl H alkyl (CH₂)_(n)COOR₆ aryl aryl alkylalkyl (CH₂)_(n)COOR₆ aryl aryl aryl alkyl (CH₂)_(n)COOR₆ aryl aryl(CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ aryl aryl (CH₂)_(n)OR₆ alkyl(CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ H alkyl (CH₂)_(n)COOR₆ aryl(CH₂)_(n)COOR₆ alkyl alkyl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ aryl alkyl(CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆aryl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ alkyl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆H alkyl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ alkyl alkyl (CH₂)_(n)COOR₆ aryl(CH₂)_(n)OR₆ aryl alkyl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆alkyl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ aryl H H H H aryl HH H alkyl aryl H H H aryl aryl H H H (CH₂)_(n)COOR₆ aryl H H H(CH₂)_(n)OR₆ aryl H H alkyl H aryl H H alkyl alkyl aryl H H alkyl arylaryl H H alkyl (CH₂)_(n)COOR₆ aryl H H alkyl (CH₂)_(n)OR₆ aryl H H arylH aryl H H aryl alkyl aryl H H aryl aryl aryl H H aryl (CH₂)_(n)COOR₆aryl H H aryl (CH₂)_(n)OR₆ aryl H H (CH₂)_(n)COOR₆ H aryl H H(CH₂)_(n)COOR₆ alkyl aryl H H (CH₂)_(n)COOR₆ aryl aryl H H(CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ aryl H H (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ arylH H (CH₂)_(n)OR₆ H aryl H H (CH₂)_(n)OR₆ alkyl aryl H H (CH₂)_(n)OR₆aryl aryl H H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ aryl H H (CH₂)_(n)OR₆(CH₂)_(n)OR₆ aryl H alkyl H H aryl H alkyl H alkyl aryl H alkyl H arylaryl H alkyl H (CH₂)_(n)COOR₆ aryl H alkyl H (CH₂)_(n)OR₆ aryl H alkylalkyl H aryl H alkyl alkyl alkyl aryl H alkyl alkyl aryl aryl H alkylalkyl (CH₂)_(n)COOR₆ aryl H alkyl alkyl (CH₂)_(n)OR₆ aryl H alkyl aryl Haryl H alkyl aryl alkyl aryl H alkyl aryl aryl aryl H alkyl aryl(CH₂)_(n)COOR₆ aryl H alkyl aryl (CH₂)_(n)OR₆ aryl H alkyl(CH₂)_(n)COOR₆ H aryl H alkyl (CH₂)_(n)COOR₆ alkyl aryl H alkyl(CH₂)_(n)COOR₆ aryl aryl H alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ aryl Halkyl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ aryl H alkyl (CH₂)_(n)OR₆ H aryl Halkyl (CH₂)_(n)OR₆ alkyl aryl H alkyl (CH₂)_(n)OR₆ aryl aryl H alkyl(CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ aryl H alkyl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ arylH aryl H H aryl H aryl H alkyl aryl H aryl H aryl aryl H aryl H(CH₂)_(n)COOR₆ aryl H aryl H (CH₂)_(n)OR₆ aryl H aryl alkyl H aryl Haryl alkyl alkyl aryl H aryl alkyl aryl aryl H aryl alkyl (CH₂)_(n)COOR₆aryl H aryl alkyl (CH₂)_(n)OR₆ aryl H aryl aryl H aryl H aryl aryl alkylaryl H aryl aryl aryl aryl H aryl aryl (CH₂)_(n)COOR₆ aryl H aryl aryl(CH₂)_(n)OR₆ aryl H aryl (CH₂)_(n)COOR₆ H aryl H aryl (CH₂)_(n)COOR₆alkyl aryl H aryl (CH₂)_(n)COOR₆ aryl aryl H aryl (CH₂)_(n)COOR₆(CH₂)_(n)COOR₆ aryl H aryl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ aryl H aryl(CH₂)_(n)OR₆ H aryl H aryl (CH₂)_(n)OR₆ alkyl aryl H aryl (CH₂)_(n)OR₆aryl aryl H aryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ aryl H aryl (CH₂)_(n)OR₆(CH₂)_(n)OR₆ aryl COOH H H H aryl COOH H H alkyl aryl COOH H H aryl arylCOOH H H (CH₂)_(n)COOR₆ aryl COOH H H (CH₂)_(n)OR₆ aryl COOH H alkyl Haryl COOH H alkyl alkyl aryl COOH H alkyl aryl aryl COOH H alkyl(CH₂)_(n)COOR₆ aryl COOH H alkyl (CH₂)_(n)OR₆ aryl COOH H aryl H arylCOOH H aryl alkyl aryl COOH H aryl aryl aryl COOH H aryl (CH₂)_(n)COOR₆aryl COOH H aryl (CH₂)_(n)OR₆ aryl COOH H (CH₂)_(n)COOR₆ H aryl COOH H(CH₂)_(n)COOR₆ alkyl aryl COOH H (CH₂)_(n)COOR₆ aryl aryl COOH H(CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ aryl COOH H (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆aryl COOH H (CH₂)_(n)OR₆ H aryl COOH H (CH₂)_(n)OR₆ alkyl aryl COOH H(CH₂)_(n)OR₆ aryl aryl COOH H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ aryl COOH H(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ aryl COOH alkyl H H aryl COOH alkyl H alkylaryl COOH alkyl H aryl aryl COOH alkyl H (CH₂)_(n)COOR₆ aryl COOH alkylH (CH₂)_(n)OR₆ aryl COOH alkyl alkyl H aryl COOH alkyl alkyl alkyl arylCOOH alkyl alkyl aryl aryl COOH alkyl alkyl (CH₂)_(n)COOR₆ aryl COOHalkyl alkyl (CH₂)_(n)OR₆ aryl COOH alkyl aryl H aryl COOH alkyl arylalkyl aryl COOH alkyl aryl aryl aryl COOH alkyl aryl (CH₂)_(n)COOR₆ arylCOOH alkyl aryl (CH₂)_(n)OR₆ aryl COOH alkyl (CH₂)_(n)COOR₆ H aryl COOHalkyl (CH₂)_(n)COOR₆ alkyl aryl COOH alkyl (CH₂)_(n)COOR₆ aryl aryl COOHalkyl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ aryl COOH alkyl (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ aryl COOH alkyl (CH₂)_(n)OR₆ H aryl COOH alkyl (CH₂)_(n)OR₆alkyl aryl COOH alkyl (CH₂)_(n)OR₆ aryl aryl COOH alkyl (CH₂)_(n)OR₆(CH₂)_(n)COOR₆ aryl COOH alkyl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ aryl COOH arylH H aryl COOH aryl H alkyl aryl COOH aryl H aryl aryl COOH aryl H(CH₂)_(n)COOR₆ aryl COOH aryl H (CH₂)_(n)OR₆ aryl COOH aryl alkyl H arylCOOH aryl alkyl alkyl aryl COOH aryl alkyl aryl aryl COOH aryl alkyl(CH₂)_(n)COOR₆ aryl COOH aryl alkyl (CH₂)_(n)OR₆ aryl COOH aryl aryl Haryl COOH aryl aryl alkyl aryl COOH aryl aryl aryl aryl COOH aryl aryl(CH₂)_(n)COOR₆ aryl COOH aryl aryl (CH₂)_(n)OR₆ aryl COOH aryl(CH₂)_(n)COOR₆ H aryl COOH aryl (CH₂)_(n)COOR₆ alkyl aryl COOH aryl(CH₂)_(n)COOR₆ aryl aryl COOH aryl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ arylCOOH aryl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ aryl COOH aryl (CH₂)_(n)OR₆ H arylCOOH aryl (CH₂)_(n)OR₆ alkyl aryl COOH aryl (CH₂)_(n)OR₆ aryl aryl COOHaryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ aryl COOH aryl (CH₂)_(n)OR₆(CH₂)_(n)OR₆ aryl NHR₆ H H H aryl NHR₆ H H alkyl aryl NHR₆ H H aryl arylNHR₆ H H (CH₂)_(n)COOR₆ aryl NHR₆ H H (CH₂)_(n)OR₆ aryl NHR₆ H alkyl Haryl NHR₆ H alkyl alkyl aryl NHR₆ H alkyl aryl aryl NHR₆ H alkyl(CH₂)_(n)COOR₆ aryl NHR₆ H alkyl (CH₂)_(n)OR₆ aryl NHR₆ H aryl H arylNHR₆ H aryl alkyl aryl NHR₆ H aryl aryl aryl NHR₆ H aryl (CH₂)_(n)COOR₆aryl NHR₆ H aryl (CH₂)_(n)OR₆ aryl NHR₆ H (CH₂)_(n)COOR₆ H aryl NHR₆ H(CH₂)_(n)COOR₆ alkyl aryl NHR₆ H (CH₂)_(n)COOR₆ aryl aryl NHR₆ H(CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ aryl NHR₆ H (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆aryl NHR₆ H (CH₂)_(n)OR₆ H aryl NHR₆ H (CH₂)_(n)OR₆ alkyl aryl NHR₆ H(CH₂)_(n)OR₆ aryl aryl NHR₆ H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ aryl NHR₆ H(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ aryl NHR₆ alkyl H H aryl NHR₆ alkyl H alkylaryl NHR₆ alkyl H aryl aryl NHR₆ alkyl H (CH₂)_(n)COOR₆ aryl NHR₆ alkylH (CH₂)_(n)OR₆ aryl NHR₆ alkyl alkyl H aryl NHR₆ alkyl alkyl alkyl arylNHR₆ alkyl alkyl aryl aryl NHR₆ alkyl alkyl (CH₂)_(n)COOR₆ aryl NHR₆alkyl alkyl (CH₂)_(n)OR₆ aryl NHR₆ alkyl aryl H aryl NHR₆ alkyl arylalkyl aryl NHR₆ alkyl aryl aryl aryl NHR₆ alkyl aryl (CH₂)_(n)COOR₆ arylNHR₆ alkyl aryl (CH₂)_(n)OR₆ aryl NHR₆ alkyl (CH₂)_(n)COOR₆ H aryl NHR₆alkyl (CH₂)_(n)COOR₆ alkyl aryl NHR₆ alkyl (CH₂)_(n)COOR₆ aryl aryl NHR₆alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ aryl NHR₆ alkyl (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ aryl NHR₆ alkyl (CH₂)_(n)OR₆ H aryl NHR₆ alkyl (CH₂)_(n)OR₆alkyl aryl NHR₆ alkyl (CH₂)_(n)OR₆ aryl aryl NHR₆ alkyl (CH₂)_(n)OR₆(CH₂)_(n)COOR₆ aryl NHR₆ alkyl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ aryl NHR₆ arylH H aryl NHR₆ aryl H alkyl aryl NHR₆ aryl H aryl aryl NHR₆ aryl H(CH₂)_(n)COOR₆ aryl NHR₆ aryl H (CH₂)_(n)OR₆ aryl NHR₆ aryl alkyl H arylNHR₆ aryl alkyl alkyl aryl NHR₆ aryl alkyl aryl aryl NHR₆ aryl alkyl(CH₂)_(n)COOR₆ aryl NHR₆ aryl alkyl (CH₂)_(n)OR₆ aryl NHR₆ aryl aryl Haryl NHR₆ aryl aryl alkyl aryl NHR₆ aryl aryl aryl aryl NHR₆ aryl aryl(CH₂)_(n)COOR₆ aryl NHR₆ aryl aryl (CH₂)_(n)OR₆ aryl NHR₆ aryl(CH₂)_(n)COOR₆ H aryl NHR₆ aryl (CH₂)_(n)COOR₆ alkyl aryl NHR₆ aryl(CH₂)_(n)COOR₆ aryl aryl NHR₆ aryl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ arylNHR₆ aryl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ aryl NHR₆ aryl (CH₂)_(n)OR₆ H arylNHR₆ aryl (CH₂)_(n)OR₆ alkyl aryl NHR₆ aryl (CH₂)_(n)OR₆ aryl aryl NHR₆aryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ aryl NHR₆ aryl (CH₂)_(n)OR₆(CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆ H H H aryl (CH₂)_(n)COOR₆ H H alkylaryl (CH₂)_(n)COOR₆ H H aryl aryl (CH₂)_(n)COOR₆ H H (CH₂)_(n)COOR₆ aryl(CH₂)_(n)COOR₆ H H (CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆ H alkyl H aryl(CH₂)_(n)COOR₆ H alkyl alkyl aryl (CH₂)_(n)COOR₆ H alkyl aryl aryl(CH₂)_(n)COOR₆ H alkyl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ H alkyl(CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆ H aryl H aryl (CH₂)_(n)COOR₆ H arylalkyl aryl (CH₂)_(n)COOR₆ H aryl aryl aryl (CH₂)_(n)COOR₆ H aryl(CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ H aryl (CH₂)_(n)OR₆ aryl(CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ H aryl (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆alkyl aryl (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆ aryl aryl (CH₂)_(n)COOR₆ H(CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ H (CH₂)_(n)COOR₆(CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ H aryl (CH₂)_(n)COOR₆ H(CH₂)_(n)OR₆ alkyl aryl (CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ aryl aryl(CH₂)_(n)COOR₆ H (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ H(CH₂)_(n)OR₆ (CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆ alkyl H H aryl(CH₂)_(n)COOR₆ alkyl H alkyl aryl (CH₂)_(n)COOR₆ alkyl H aryl aryl(CH₂)_(n)COOR₆ alkyl H (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ alkyl H(CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆ alkyl alkyl H aryl (CH₂)_(n)COOR₆ alkylalkyl alkyl aryl (CH₂)_(n)COOR₆ alkyl alkyl aryl aryl (CH₂)_(n)COOR₆alkyl alkyl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ alkyl alkyl (CH₂)_(n)OR₆aryl (CH₂)_(n)COOR₆ alkyl aryl H aryl (CH₂)_(n)COOR₆ alkyl aryl alkylaryl (CH₂)_(n)COOR₆ alkyl aryl aryl aryl (CH₂)_(n)COOR₆ alkyl aryl(CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ alkyl aryl (CH₂)_(n)OR₆ aryl(CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ H aryl (CH₂)_(n)COOR₆ alkyl(CH₂)_(n)COOR₆ alkyl aryl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ aryl aryl(CH₂)_(n)COOR₆ alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆alkyl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆H aryl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ alkyl aryl (CH₂)_(n)COOR₆ alkyl(CH₂)_(n)OR₆ aryl aryl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆aryl (CH₂)_(n)COOR₆ alkyl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆aryl H H aryl (CH₂)_(n)COOR₆ aryl H alkyl aryl (CH₂)_(n)COOR₆ aryl Haryl aryl (CH₂)_(n)COOR₆ aryl H (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ arylH (CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆ aryl alkyl H aryl (CH₂)_(n)COOR₆ arylalkyl alkyl aryl (CH₂)_(n)COOR₆ aryl alkyl aryl aryl (CH₂)_(n)COOR₆ arylalkyl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ aryl alkyl (CH₂)_(n)OR₆ aryl(CH₂)_(n)COOR₆ aryl aryl H aryl (CH₂)_(n)COOR₆ aryl aryl alkyl aryl(CH₂)_(n)COOR₆ aryl aryl aryl aryl (CH₂)_(n)COOR₆ aryl aryl(CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ aryl aryl (CH₂)_(n)OR₆ aryl(CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ H aryl (CH₂)_(n)COOR₆ aryl(CH₂)_(n)COOR₆ alkyl aryl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ aryl aryl(CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆ (CH₂)_(n)COOR₆ aryl (CH₂)_(n)COOR₆aryl (CH₂)_(n)COOR₆ (CH₂)_(n)OR₆ aryl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ Haryl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ alkyl aryl (CH₂)_(n)COOR₆ aryl(CH₂)_(n)OR₆ aryl aryl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ (CH₂)_(n)COOR₆aryl (CH₂)_(n)COOR₆ aryl (CH₂)_(n)OR₆ (CH₂)_(n)OR₆

The invention also relates to a method for the preparation ofradiolabeled biomolecules comprising:

a) contacting a chelating agent of the invention with a carbonyl moietyof the formula [M(CO)₃]⁺, wherein M is rhenium (Re) or technetium (Tc),under conditions for forming a chelator-carbonyl complex; and

b) contacting the complex with a biomolecule for obtaining aradiolabeled biomolecule. This method is in particular useful forlabeling biomolecules that are sensitive to temperature and extreme pH.

This method can for example be performed with a kit, comprising a firstvial with the chelating agent of the invention, optionally a firstreaction vial for contacting the chelating agent with the carbonylmoiety, a second vial with the biomolecule and optionally a secondreaction vial for reacting the biomolecule with the chelator-carbonylcomplex obtained in the first step of the reaction.

In an alternative embodiment the invention provides a method for thepreparation of radiolabeled biomolecules comprising:

a) contacting a chelating agent of the invention with a biomolecule forobtaining a chelator-biomolecule; and

b) contacting the chelator-biomolecule with a carbonyl moiety of theformula [M(CO)₃]⁺, wherein M is rhenium (Re) or technetium (Tc) underconditions for forming a radiolabeled biomolecule.

A kit for performing this method comprises for example a first vial withthe chelating agent of the invention, optionally a first reaction vialfor reacting the chelating agent with the biomolecule, a second vialwith the carbonyl moiety and optionally a second reaction vial forreacting the chelator-biomolecule obtained in the first step of thereaction with the carbonyl.

The invention will be further illustrated in the example that follows.

EXAMPLE INTRODUCTION

The bifunctional pyrazolyl-polyamines, pyrazolyl-polythioether,pyrazolyl amino-thioether ligands, pyrazolyl-aminophosphines andpyrazolyl-thioetherphosphines contain different donor atom sets tostabilize the metal and have different functional groups in differentpositions to which seeking molecules such as, for example, monoclonalantibodies, peptides, oligonucleotides and glycoproteins, can becoupled. They can also have different substituents and alkyl chains indifferent positions of the backbone for tuning the physico-chemicalproperties of the molecules.

A general overview is given in FIG. 1, showing possible combinations formetal fragments of the type [M(CO)₃]⁺ (M=Re, Tc, Mn). The five differenttypes of bifunctional tridentate pyrazolyl-containing ligands, which aresubject of this invention are depicted schematically in FIG. 2.

The present invention will be further illustrated in the FIGS. 3-6,which are solely intended to clarify the invention. This family ofligands led to thermodynamically stable complexes and the versatility ofthe backbone is an important factor for tuning the physico-chemicalproperties of the compounds and obviously its pharmacokinetics. In FIG.6, some of the Re and Tc complexes referred as examples areschematically represented.

Materials and Methods

1. Synthesis of 2-[2-(pyrazol-1-yl)ethylimino]ethylamine(pz(CH₂)₂NH(CH₂)₂NH₂) (1) (see FIG. 3)

A solution of 1-(2-bromoethyl)pyrazole [6d] (12 mmol) in tetrahydrofuranwas added dropwise to a solution of ethylenediamine (0.24 mol) in water.The mixture was refluxed for 4 hours. The THF was removed under vacuumand the water phase was washed with dichloromethane. After drying undervacuum resulted a yellow oil which was formulated as pz(CH₂)₂NH(CH₂)₂NH₂(1).

Yield: 50%

¹H-NMR (D₂O): 7.53 (d, H(3)pz, 1H); 7.45 (d, H(5)pz, 1H); 6.23 (t,H(4)pz, 1H); 4.14 (t, CH₂, 2H); 2.91 (t, CH₂, 2H); 2.77 (t, CH₂, 2H);2.62 (t, CH₂, 2H).

2. Synthesis pz(CH₂)₂N[(CH₂)₃COOH](CH₂)₂NH₂ (4) (see FIG. 3)

2.1. BOC-ON Protection

A solution of 1 (1.1 g; 7 mmol) in DMF (20 ml) was cooled to 0° C. and asolution of BOC-ON (1.7 g; 7 mmol) in DMF (20 ml) was added dropwise.The reaction mixture was stirred for 3 hours at 0° C. The solvent wasremoved under vacuum and the solid residue was dissolved in water andwashed with chloroform 3 times, yielding 2 as an oil. Yield: 68%. ¹H-NMR(D₂O): 7.55 (d, H(3)pz, 1H); 7.47 (d, H(5)pz, 1H) ; 6.24 (t, H(4)pz,1H); 4.38 (t, CH₂, 2H); 3.40 (t, CH₂, 2H); 3.20 (t, CH₂, 2H); 2.99 (t,CH₂, 2H); 1.25 (s, CH₃, 9H).

2.2. Alkylation with Ethyl 4-bromobutyrate, Hydrolysis and Deprotection

Compound 2 (757 mg; 3 mmol) was dissolved in 10 ml of acetonitrile.Potassium carbonate (829 mg; 6 mmol) and a catalytic amount of potassiumiodide were added to the solution, and ethyl 4-bromobutyrate (858 ml, 16mmol) was added dropwise. After refluxing for 3 days, the supernatantwas separated by filtration and vacuum dried leading to 3. This compound(733 mg, 2 mmol) was dissolved in an aqueous solution of NaOH (800 mg,20 mmol) and reacted for one day at room temperature. The solution wasthen neutralized with HCl 1N and vacuum dried. The solid residue wasdissolved in methanol, the precipitating salts were filtered off, andthe solvent was removed under vacuum, yielding a yellow/brown oilformulated as 4. Yield: (50%).

¹H-NMR (D₂O): 7.78 (d, H(3)pz, 1H); 7.64 (d, H(5)pz, 1H); 6.42 (t,H(4)pz, 1H); 4.36 (t, CH₂, 2H); 3.10 (t, CH₂, 2H); 3.02 (t, CH₂, 2H);2.86 (t, CH₂, 2H); 2.64 (t, CH₂, 2H); 2.15 (t, CH₂, 2H) ; 1.68 (q, CH₂,2H)

3. Synthesis (4-carboxylic)pz(CH₂)₂NH(CH₂)₂NH₂ (7) (see FIG. 3)

3.1. Ethyl N-2-hydroxyethyl-4-pyrazolecarboxylate (5)

Compound 5 was prepared using the classical approach for preparingpyrazoles [7]. Ethyl 2-formyl-3-oxopropionate (2.80 g; 20 mmol) wasdissolved in 20 ml of ethanol and cooled to 0° C.2-Hydroxyethylhydrazine (1.44 g; 20 mmol) was dissolved in 100 ml ofethanol and was added dropwise to the solution of ethyl2-formyl-3-oxopropionate. The reaction mixture was left overnight atroom temperature. The solvent was vacuum removed yielding a yellow oil.Yield: 95%

¹H-NMR (CDCl₃): 7.93 (s, H(3)pz, 1H); 7.91 (s, H(5)pz, 1H); 4.30-4.22(m, CH₂+OCH₂, 5H); 3.99 (t, CH₂, 2H); 1.30 (t, CH₃, 3H).

3.2. Ethyl N-(2-p-toluenesulfonylethyl)-4-pyrazolecarboxylate (6)

Ethyl N-2-hydroxyethyl-4-pyrazolecarboxylate (5) (2.76 g, 15 mmol) andp-toluenesulfonylchloride (2.85 g, 15 mmol) were suspended in a solutionof acetone (15 ml) and water (15 ml) and cooled to 0° C. A solution ofNaOH (0.6 g, 15 mmol) in water (10 ml) was added dropwise for 15 min.The mixture was then allowed to reach the room temperature and wasvigorously stirred overnight. The acetone was evaporated and the aqueoussolution was extracted 3 times with chloroform, yielding a yellow oil.Yield: 60%

¹H-NMR (CDCl₃): 7.82 (s, H(3)pz, 1H); 7.76 (s, H(5)pz, 1H); 7.61 (d,H(ph), 2H); 7.26 (d, H(ph), 2H); 4.35 (q, OCH₂, 2H); 4.24 (t, CH₂, 2H);2.15 (s, CH₃, 3H); 1.33 (t, CH₂, 2H).

Compound 7 was prepared as follows. Ethylenediamine (16 ml; 0.24 mol)was dissolved in a solution of NaOH (9.6 g; 0.24 mol) in water (20 ml).A solution of Ethyl N-(2-p-toluenesulfonylethyl)-4-pyrazolecarboxylate(6) (4.06 g; 12 mmol) in THF (10 ml) was added dropwise to theethylenediamine solution. The reaction mixture was refluxed for 24hours. After that, the solvent was vacuum removed and the product waspurified by column chromatography in silica-gel(eluent:methanol-NH₃/methanol (50:50)), yielding a dark yellow solid.Yield: 50%.

¹H-NMR (D₂O): δ 7.80 (s, H(3)pz, 1H); 7.64 (s, H(5)pz, 1H); 4.27 (t,CH₂, 2H); 3.24 (t, CH₂, 2H); 3.11-3.00 (m, 2CH₂, 4H). IV (KBr) (ν/cm⁻¹):1690 (C═O).

4. Synthesis of 3,5-Mepz(CH₂)₂N[(CH₂)₃GlyGlyOEt)](CH₂)₂NH₂ (13) (FIG. 4)

4.1. BOC-ON Protection (9)

Compound 8 (3.41 g, 18.71 mmol) [4c] was dissolved in THF (25 mL) andcooled to a temperature between −10° C. and 0° C. BOC-ON (4.60 g, 18.71mmol) in THF (20 ml) was added dropwise and the reaction mixture wasstirred for 2 h at 0° C., resulting in the complete conversion of 8 asmonitored by TLC (R_(f)=0.5, 100% MeOH). The reaction mixture was thenwarmed to room temperature and partitioned between a saturated aqueousNa₂CO₃ solution and dichloromethane. The organic layer was separated,dried over anhydrous MgSO₄, filtered, and concentrated under reducedpressure to afford the product 9 in quantitative yield (by ¹H-NMR), as ahighly viscous colorless oil. This product was used in the next stepwithout further purification.

¹H-NMR (CDCl₃): δ5.76 (s, pyrazol, 1H), 5.08 (s br., NH, 1H), 4.04 (t,CH₂, 2H), 3.18 (m, CH₂, 2H), 2.99 (t, CH₂, 2H), 2.72 (t, CH₂, 2H), 2.18(s, CH₃, 3H), 2.20 (s, CH₃, 3H), 1.40 (s, C(CH₃)₃, 9H).

4.2. Synthesis of 3,5-Me₂pz(CH₂)₂N[(CH₂)₃COOH](CH₂)₂NHBOC (11)

To a stirred solution of the crude product 9 (1.02 g) in CH₃CN (15 mL),ethyl 4-bromobutyrate (1.4 g, 7.20 mmol), K₂CO₃ (1.00 g, 7.20 mmol) anda catalytic amount of KI were added. The obtained suspension was allowedto react under vigorous stirring for 11 days, being the reactionmonitored by TLC (R_(f) product=0.4, 10% MeOH/CH₂Cl₂) . Afterelimination of the white solids in suspension by filtration, the solventwas evaporated in vacuum and a pale-yellow viscous oil was obtained. Thecrude product was chromatographed on an appropriate column of silica gelwith 75-100% ethyl acetate/hexane (gradient) to afford 10 as apale-yellow viscous oil, which solidifies on standing for several daysat room temperature. Yield: 0.73 g (51% yield).

A solution of 10 (4.6 g, 11.60 mmol) in THF (190 mL) and aqueous NaOH(8.3 mL of a 14 N NaOH solution, 116.0 mmol) was refluxed for 8 h. Thereaction was monitored by TLC (R_(f) product=0.2, 10% MeOH/CH₂Cl₂).After neutralization with HCl 4N (pH 6-7), the THF/H₂O solution wasevaporated to dryness under reduced pressure. The crude product waschromatographed on an appropriate column of silica gel with 10-50%MeOH/CHCl₃ (gradient) to afford 11 as an highly viscous colorless oil,which crystallizes on standing after several days. Yield: 2.82 g (66%).

Compound 10: ¹H-NMR (CDCl₃): δ 5.75 (s, pyrazol, 1H), 4.09 (q, CH₂, 2H),3.98 (s br., CH₂, 2H), 3.08 (s br., CH₂, 2H), 2.78 (s br., CH₂, 2H),2.45-2.51 (m, CH₂, 4H), 2.23 (s, CH₃, 3H), 2.18 (m, CH₃, CH₂, 5H), 1.63(s br., CH₂, 2H), 1.41 (s, C(CH₃)₃, 9H), 1.23 (t, CH₃, 3H).

Compound 11: ¹H-NMR (CDCl₃): δ 5.81 (s, pyrazol, 1H), 4.93(s br., NH,1H) 4.12 (t br., CH₂, 2H), 3.04 (q br., CH₂, 2H), 2.86 (t br., CH₂, 2H),2.58-2.64 (m, CH₂, 4H), 2.42 (t, CH₂, 2H), 2.24 (s, CH₃, 3H), 2.19 (s,CH₃, 3H), 1.79 (m, CH₂, 2H), 1.40 (s, C(CH₃)₃, 9H).

Compound 3,5-Me₂pz (CH₂)₂N [ (CH₂)₃CONHGlyGlyOEt](CH₂)₂NH₂ (13) wasprepared as follows (see FIG. 4).

To a solution of 11 (1.51 g, 4.09 mmol) in CH₃CN (48 mL) were addedGlyGly ethyl ester hydrochloride (0.57 g, 4.09 mmol), triethylamine(1.24g, 12.27 mmol), and HBTU (1.55 g, 4.09 mmol). The reaction mixturewas stirred 20 h at room temperature under nitrogen. The reaction wasmonitored by TLC (R_(f) product=0.8, 20% MeOH/CH₂Cl₂). The solvent wasevaporated and the crude product obtained was purified by chromatographyon an appropriate silica gel column with 3-5% MeOH/CHCl₃ (gradient) toafford 12 as a viscous colorless oil. Yield: 1.23 g (59%).

A solution of 3,5-Me₂pz(CH₂)₂N[(CH₂)₃CONHGlyGlyOEt](CH₂)₂NHBOC (12)(1.23 g, 2.41 mmol) in CH₂Cl₂/TFA (25 mL/4.1 mL) was allowed to reactfor 2 h. The reaction was monitored by TLC (R_(f)=0.4, 20% MeOH/CH₂Cl₂). The solvent and the TFA were evaporated under reduced pressure and ahighly viscous pale-yellow oil was obtained. This oil was dissolved inwater, neutralized with NaOH 1N (pH 7-8) and the solvent evaporated todryness. TLC: R_(f)=0.2, 20% MeOH/CH₂Cl₂ The compound was furtherpurified by chromatography on an appropriate silica gel column with20-40% MeOH/CHCl₃ (gradient) to afford 13 as a viscous colorless oil.Yield: 0.97 g (98%).

Compound 12: ¹H-NMR (CDCl₃): δ 8.66 (s br., NH, 1H), 7.00 (s br., NH,1H), 5.80 (s, pyrazol, 1H), 4.91 (s br., NH, 1H) 4.15 (q., CH₂, 2H),4.04 (s br., CH₂, 2H), 3.97 (d, CH₂, 2H), 3.90 (d, CH₂, 2H), 2.89 (sbr., CH₂, 2H), 2.69 (s br., CH₂, 2H), 2.51 (s br., CH₂, 2H), 2.39 (sbr., CH₂, 2H), 2.30 (s br., CH₂, 2H), 2.20 (s, CH₃, 3H), 2.18 (s, CH₃,3H), 1.74 (s br., CH₂, 2H), 1.38 (s, C(CH₃)₃, 9H), 1.23 (t, CH₃, 3H)

Compound 13: ¹H-NMR (CD30D): δ 5.84 (s, pyrazol, 1H), 4.17 (q, CH₂, 2H),4.06 (t, CH₂, 2H), 3.91 (d, CH₂, 4H), 2.97 (t, CH₂, 2H), 2.71-2.80 (m,CH₂, 4H), 2.51 (t, CH₂, 2H), 2.25 (s, CH₃, 3H), 2.15 (s, CH₃, 3H), 2.12(t, CH₂, 2H), 1.66 (m, CH₂, 2H), 1.25 (t, CH₃, 3H).

5. Synthesis of 3,5-Mepz(CH₂)₂S(CH₂)₂S(CH₂)COOEt (16) (FIG. 5)

5.1 Synthesis of 3,5-Mepz(CH₂)₂S(CH₂)₂OH (14)

0.70 ml (10 mmol) of HSCH₂CH₂OH were mixed with 0.40 g (10 mmol) ofNaOH, in water, and the solution was refluxed for 5 min. To thissolution, 2.78 g (10 mmol) ofN-(2-p-toluenesulfonylethyl)-3,5-dimethylpyrazole dissolved intetrahydrofuran (THF) were added dropwise at room temperature, followedby gentle reflux for 3 hr. The mixture was extracted with chloroformfrom which, after drying under vacuum, were recovered 1.62 g of 14 as ayellow oil (8.10 mmol, 81%).

Compound 14: ¹H-NMR (CDCl₃): 5.67 (s, pz-H, 1H); 4.39 (s, OH, 1H); 4.03(t, CH₂, 2H); 3.60 (t, CH₂, 2H); 2.83 (t, CH₂, 2H); 2.50 (t, CH₂, 2H);2.14 (s, CH₃, 3H); 2.09 (s, CH₃, 3H).

5.2 Synthesis of 3,5-Mepz(CH₂)₂S(CH₂)₂Br (15)

0.19 ml (2 mmol) of PBr₃ were added to 14 (0.40 g, 2 mmol) dissolved inchloroform, and the resulting solution was refluxed for 24 hours underN₂. The mixture was treated with 20 ml of 10% NaHCO₃ solution. Theorganic phase was separated and chloroform removed under vacuum,yielding 0.329 g of 15 as a yellow oil (1.25 mmol, 63% ).

¹H-NMR (CD_(c13)): 5.82 (s, pz-H, 1H); 4.15 (t, CH₂, 2H); 3.36 (t, CH₂,2H); 3.00 (t, CH₂, 2H); 2.70 (t, CH₂, 2H); 2.26 (s, CH₃, 3H); 2.23 (s,CH₃, 3H).

Under N₂, dry ethanol was added to metallic sodium (0.15 g, 4.56 mmol),and the mixture was stirred at room temperature until completeconversion to sodium ethoxide. To this mixture an ethanolic solution ofethyl 2-mercaptoacetate (0.50 ml, 4.56 mmol) was added dropwise,followed by addition of 1.20 g (4.56 mmol) of 3,5-Mepz(CH₂)₂S(CH₂)₂Br(15) in ethanol. The reaction mixture was stirring overnight at roomtemperature. After this time, the solvent was removed under vacuum andthe resulting oil was dissolved in chloroform. After washing with water,the organic phase was dried under vacuum yielding 1.00 g of 16 as ayellow oil (3.3 mmol, 72.4%).

Compound 16: ¹H-NMR (CDCl₃): 5.82 (s, pz-H, IH); 4.14 (m, CH2, CH₂—COO,4H); 3.25 (s, CH₂, 2H); 2.92 (t, CH₂, 2H); 2.75 (t, CH₂, 2H); 2.57 (t,CH₂, 2H); 2.2 (s, CH₃, 3H); 2.16 (s, CH₃, 3H); 1.25 (t, CH₃, 3H).

6. Re and Tc Compounds (see FIG. 6)

6.1. Synthesis of (Re(CO)₃(κ³-pz(CH₂)₂NH(CH₂)₂NH₂)]Br (17a)

100 mg (0.130 mmol) of (NEt₄)₂[ReBr₃(CO)₃] were mixed with 20 mg (0.130mmol) of the compound 1 (pz(CH₂)₂NH(CH₂)₂NH₂) in water, and the solutionwas refluxed for 2 hours. The volume was then reduced under vacuum, andthe mixture was left at 4° C. until a white solid precipitated.

Yield: >90% by ¹H-NMR

¹H-NMR (D₂O): 7.82 (d, H(3)pz, 1H); 7.76 (d, H(5)pz, 1H); 6.54 (s br,NH, 1H); 6.39 (t, H(4)pz, 1H); 4.86 (s, largo, NH₂, 1H); 4.43 (m, CH₂,1H); 4.16 (m, CH₂, 1H); 3.94 (s, largo, NH₂, 1H); 3.50 (m, CH₂, 1H);2.87 (m, CH₂, 1H); 2.71 (m, CH₂, 2H); 2.48 (m, CH₂, 1H) ; 2.08 (m, CH₂,1H)

6.2. Synthesis of [^(99m)Tc(CO)₃(κ³-pz(CH₂)₂NH(CH₂)₂NH₂)]+ (17b)

100 μl of a solution of compound 1 (pz(CH₂)₂NH(CH₂)₂NH₂) 10⁻⁴ M wasadded to 1 ml of a solution of [^(99m)Tc(OH)₃(CO)₃]+ (1-2 mCi) inphosphate buffer. The solution was incubated for 30 min at 100° C. andthen analyzed by HPLC. The radiochemical purity was >90%.

6.3. Synthesis of [Re(CO)₃(κ³-(4-carboxylic acid)pz(CH₂)₂NH(CH₂)₂NH₂)]Br(18a)

100 mg (0.130 mmol) of (NEt₄)₂[ReBr₃(CO)₃] were mixed with 26 mg (0.130mmol) of compound 7, in water, and the solution was refluxed for 2hours. The volume was then reduced under vacuum, and the mixture wasleft at 4° C. until a white solid precipitated.

Yield: >90% by ¹H-NMR

¹H-NMR (D₂O): δ 8.22 (s, H(3)pz, 1H); 8.20 (s, H(5)pz, 1H); 6.62 (s,largo, NH, 1H); 4.94 (s, largo, NH₂, 1H); 4.43 (m, CH₂, 1H); 4.25 (m,CH₂, 1H); 4.05 (s, largo, NH₂, 1H); 3.52 (m, CH₂, 1H); 2.92 (m, CH₂,1H); 2.76 (m, CH₂, 2H); 2.53 (m, CH₂, 1H) ; 2.14 (m, CH₂, 1H) IV (KBr)(ν/cm⁻¹): 2010 (C═O); 1885 (C═O); 1690 (C═O ligando)

6.4. Synthesis of [Re(CO)₃(κ³-3,5-Me₂pz(CH₂)₂N(CH₂)₂(glygly)NH₂)]Br(19a)

100 mg (0.130 mmol) of (NEt4)₂[ReBr₃(CO)₃] were mixed with 53 mg (0.130mmol) of the ligand 13, in water, and the 5 solution was refluxedovernight.

Yield: 100% by ¹H-NMR

¹H-NMR (D₂O): δ 6.04 (s, H(4)pz, 1H); 5.05 (s, br, NH₂, 1H); 4.36-4.31(m, CH₂, 1H); 4.16-4.04 (m, CH₂, 1H); 3.88 (s, NHCH₂CO, 2H); 3.84 (s,NHCH₂CO, 2H); 3.65 (s, br, NH₂, 1H); 3.53 (m, CH₂, 1H); 3.30 (m, CH₂,2H); 2.86 (m, CH₂, 1H); 2.74 (m, CH₂, 2H); 2.57 (m, CH₂, 1H); 2.40 (m,CH₂, 1H); 2.31 (m, CH₂, 1H); 2.73 (s, CH₃, 3H); 2.16 (s, CH₃, 3H); 2.10(m, CH₂, 1H); 1.95 (m, CH₂, 1H).

6.5. Synthesis of [^(99m)Tc(CO)₃(κ³-3,5-Me₂pz(CH₂)₂N(CH₂)₂(glygly)NH₂)]⁺(19b)

100 ml of a solution of 13 (10⁻³ M) was added to 1 ml of a solution of[^(99m)Tc(OH)₃(CO)₃]⁺ (1-2 mCi) in phosphate buffer. The solution wasincubated for 1 h at 100° C. and then analysed by HPLC. Theradiochemical purity was >90%.

7. Synthesis of pyrazolyl-aminophosphines (FIG. 7)

The preparation of the pyrazolyl-aminophosphines of the inventioninvolves alkylation of 1-(2-aminoethyl)pyrazoles with(2-bromoethyl)phosphonic acid diethyl esther, yielding apyrazole-amino-phosphonate derivative (compound a). Reduction ofcompound a with lithium aluminium hydride (LAH) affords a primaryphoshine (compound b) which is then converted to the final chelator(compound c) 30 by treatment with formaldehyde in acidic medium (Kattiet al., J. Am. Chem. Soc. 122, 1554 (2000).

8. Synthesis of pyrazolyl-thioetherphosphines (FIG. 8)

The preparation of pyrazolyl-thioetherphosphines of the inventioninvolves reaction of 1-(2-mercaptoethyl)pyrazoles with(2-bromoethyl)phosphonic acid diethyl esther yielding apyrazole-thioether-phosphonate derivative (compound d) (Katti et al.,Angew. Chem. Int. Ed. 38, 2020 (1999). Reduction of compound d withlithium aluminium hydride, followed by treatment of the resultingprimary phoshine (compound e) with formaldehyde in acidic medium affordsthe final chelator (compound f).

REFERENCES

-   [1] a) Alberto et al WO 98/48848,    -   b) Alberto et al., WO 00/50086,    -   c) Alberto et al., WO 01/00637    -   d) Alberto et al, U.S. Pat. No. 6,344,178 B1-   [2] a) Hilger et al, U.S. Pat. No. 6,488,909 B1.-   [3] a) Alberto et al, Polyhedron 17 (1998) 1303    -   b) Alberto et al., J. Med. Chem. 41 (1998) 4429    -   c) Alberto et al, J. Am. Chem. Soc. 121 (1999) 6076    -   d) Alberto et al, J. Nucl. Med. 40 (1999) 1913    -   e) Schibli et al, Nucl. Med. and Biol. 26 (1999) 711    -   f) Alberto et al, Bioconjugate Chem. 11 (2000) 414    -   g) Alberto et al, Bioconjugate Chem. 11 (2000) 345    -   h) Alberto et al., Chem. Eur. Journal 7 (2001) 1868    -   i) Alberto et al, Angew. Chem. Int. Ed. 40 (2001) 3062    -   j) Alberto et al, Bioconjugate Chem. 13 (2002) 750.-   [4] a) Santos et al, J. Am. Chem. Soc. 122 (2000) 11240    -   b) Santos et al., Inorg. Chem. 40 (2001) 5147    -   c) Santos et al, J. Chem. Soc. Dalton Trans.(2002) 4714.-   [5] a) Valliant et al, Inorg Chem. Commun. 41 (2002) 628    -   b) Valliant et al, Inorg Chem. 41 (2002) 6417-   [6] a) Sorrell et al, Inorg. Chem. 22 (1983) 1883    -   b) Driessen et al. J. Chem. Soc. Dalton Trans. (1992) 481    -   c) Parkin et al., Inorg. Chem. 35 (1996) 2415    -   d) Ballesteros et al., Bioorganic and Medicinal Chem. 7 (1999)        517.    -   e) Bouwman et al., Inorg. Chim. Acta (2000) 183-   [7] Holzer et al, J. Heterocyclic Chem. 130 (1993) 865

1. Chelating agent of the general formula:

wherein m is 0 or 1; X is NR₄ or S; Y is SR₅, NHR₅ or P(R₅)₂; R₁ and R₃are the same or different and are selected from H, alkyl or aryl; R₂ isCOOH, NHR₆ or (CH₂)_(n)COOR₆; R₄ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or(CH₂)_(n)OR₆; R₅ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆ R₆ isH, a biomolecule, alkyl or aryl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.2. Chelating agent as claimed in claim 1, wherein the alkyl is a C₁alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl.
 3. Chelatingagent as claimed in claim 2, wherein the alkyl is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, isohexyl (2-methylpentyl), neohexyl(2,2-dimethylbutyl), 3-methylpentyl, 2,3-dimethylbutyl.
 4. Chelatingagent as claimed in claim 1, wherein the aryl is monocyclic orpolycyclic, C₁₀-C₁₈, and optionally substituted with one or more groupsselected from alkyl, carboxy, oxo, amino, alkoxy and aldehyde. 5.Chelating agent as claimed in claim 4, wherein the aryl is phenyl orbenzyl.
 6. Chelating agent as claimed in claim 1, wherein n is 2, 3, 4,5 or
 6. 7. Chelating agent as claimed in claim 1, which agent is apyrazolyl-polyamine of the general formula:

wherein R₁, R₂, R₃, R₄ and R₅ are as defined in claim
 1. 8. Chelatingagent as claimed in claim 1, which agent is a pyrazolyl-aminothioetherof the general formula:

wherein R₁, R₂, R₃, R₄ and R₅ are as defined in claim
 1. 9. Chelatingagent as claimed in claim 1, which agent is a pyrazolyl-polythioether ofthe general formula:

wherein R₁, R₂, R₃, R₄ and R₅ are as defined in claim
 1. 10. Chelatingagent as claimed in claim 1, which agent is a pyrazolyl-aminophosphineof the general formula:

wherein R₁, R₂, R₃, R₄ and R₅ are as defined in claim
 1. 11. Chelatingagent as claimed in claim 1, which agent is apyrazolyl-thioetherphosphine of the general formula:

wherein R₁, R₂, R₃, R₄ and R₅ are as defined in claim
 1. 12. Chelatingagent as claimed in claim 1, wherein X and Y are N, R₆ is H, C₁ alkyl,C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl, phenyl, benzyl or abiomolecule.
 13. Chelating agent as claimed in claim 1, wherein X and Yare S, R₆ is H, C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl or C₆alkyl, phenyl, benzyl or a biomolecule.
 14. Chelating agent as claimedin claim 1, wherein X is N, Y is S, R₆ is H, C₁ alkyl, C₂ alkyl, C₃alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl, phenyl, benzyl or a biomolecule.15. Chelating agent as claimed in claim 1, wherein X is S, Y is N, R₆ isH, C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl, phenyl,benzyl or a biomolecule.
 16. Chelating agent as claimed in claim 1,wherein X is S, Y is P(R₅)₂, R₆ is H, C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄alkyl, C₅ alkyl or C₆ alkyl, phenyl, benzyl or a biomolecule. 17.Chelating agent as claimed in claim 1, wherein X is N, Y is P(R₅)₂, R₆is H, C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl,phenyl, benzyl or a biomolecule.
 18. Chelating agent as claimed in claim1, wherein R₆ is a biomolecule.
 19. Chelating agent as claimed in claim18, wherein the biomolecule is selected from amino acids, peptides,proteins, oligonucleotides, polynucleotides, and sugars.
 20. Chelatingagent as claimed in claim 19, wherein the biomolecule is selected fromthe group consisting of antibodies and ligands of tumor receptors. 21.Chelating agent as claimed in claim 19, wherein the biomolecule isselected from the group consisting of CCK, thioglucose, glucosamine,somatostatin, neurotensin, bombesin, CCK, annexin, interleukins, growthfactors, steroid hormones and molecules binding to GPIIb/IIIa receptors.22. Chelating agent as claimed in claim 19, wherein the biomolecule isselected from the group consisting of glucose, thioglucose, andneurotransmitters.
 23. Chelating agent as claimed in claim 19, whereinthe biomolecule is an inhibitor of the tyrosine kinase activity. 24.Chelating agent as claimed in claim 1, which agent is a compound of thefollowing formula:


25. Chelating agent as claimed in claim 1, which agent is a compound ofthe following formula:


26. Chelating agent as claimed in claim 1, which agent is a compound ofthe following formula:

27-35. (canceled)
 36. Chelating agent of the general formula:

wherein m is 0 or 1; X is NR₄ or S; Y is SR₅, NHR₅ or P(R₅)₂; R₁ and R₃are the same or different and are selected from H, alkyl or aryl; R₂ isH, COOH, NHR₆ or (CH₂)_(n)COOR₆; R₄ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or(CH₂)_(n)OR₆; R₅ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆ R₆ isH, a biomolecule, alkyl or aryl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,wherein at least one of R₁, R₃, R₄, R₅, and R₆ is phenyl or benzyl. 37.Chelating agent of the general formula:

wherein m is 0 or 1; X is NR4 or S; Y is P(R₅)₂; R₁ and R₃ are the sameor different and are selected from H, alkyl or aryl; R₂ is H, COOH, NHR₆or (CH₂)₆COOR₆; R₄ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆; R₅is H, alkyl, aryl, (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆ R₆ is H, abiomolecule, alkyl or aryl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 r
 10. 38.Chelating agent of the general formula:

wherein m is 0 or 1; X is NR₄ or S; Y is SR₅, NHR₅ or P(R₅)₂; R₁ and R₃are the same or different and are selected from H, alkyl or aryl,wherein at least one of R₁ and R₃ is aryl; R₂ is H, COOH, NHR6 or(CH₂)_(n)COOR₆; R₄ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆; R₅is H, alkyl, aryl, (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆ R₆ is H, abiomolecule, alkyl or aryl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9or
 10. 39.Chelating agent of the general formula:

wherein m is 0 or 1; X is NR₄; Y is SR₅, NHR₅ or P(R₅)₂; R₁ and R₃ arethe same or different and are selected from H, alkyl or aryl; R₂ is H,COOH, NHR₆ or (CH₂)_(n)COOR₆; R₄ is aryl, (CH₂)_(n)COOR₆ or(CH₂)_(n)OR₆; R₅ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆ R₆ isH, a biomolecule, alkyl or aryl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.40. Chelating agent of the general formula:

wherein m is 0 or 1; X is NR₄ or S; Y is SR₅, NHR₅ or P(R₅)₂; R₁ and R₃are the same or different and are selected from H, alkyl or aryl; R₂ isH, COOH, NHR₆ or (CH₂)_(n)COOR₆; R₄ is H, alkyl, aryl, (CH₂)_(n)COOR₆ or(CH₂)_(n)OR₆; R₅ is (CH₂)_(n)COOR₆ or (CH₂)_(n)OR₆ R₆ is H, abiomolecule, alkyl or aryl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.